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Polyethylene glycol compounds and process for makingRelated Patent Categories: Synthetic Resins Or Natural Rubbers -- Part Of The Class 520 Series, Natural Rubber Compositions Having Nonreactive Materials (dnrm) Other Than: Carbon, Silicon Dioxide, Glass Titanium Dioxide, Water, Hydrocarbon, Halohydrocarbon, Ethylenically Unsaturated Reactant Admixed With A Preformed Reaction Product Derived From: (a) At Least One Polycarboxylic Acid, Ester, Or Anhydride; (b) At Least One Polyhydroxy Compound; And (c) At Least One Fatty Acid Glycerol Ester, Or A Fatty Acid Or Salt Derived From A Naturally Occurring Glyceride, Tall Oil, Or A Tall Oil Fatty Acid, Solid Polymer Is Derived From 1,2-epoxy Compound Containing Only One 1,2 Epoxy Group As Sole Reactant And Wherein None Of The Reactants Contains A Plurality Of Methylol Groups Or Derivatives ThereofPolyethylene glycol compounds and process for making description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060074200, Polyethylene glycol compounds and process for making. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND [0001] The instant invention relates to polyethylene glycol compounds and a process for making such compounds. More particularly, the instant invention relates to high molecular weight polyethylene glycol compounds having narrow molecular weight distribution and a process for making such compounds. The polyethylene glycol compounds of the instant invention are useful for chemical modification of physiologically active materials, which modified materials are applicable, for example, in drug delivery systems. [0002] Biologically active compounds conjugated with polyoxyalkylenes can provide enhanced biocompatibility for the compound, See, for example, U.S. Pat. No. 5,366,735 and U.S. Pat. No. 6,280,745. A review of this subject by Zalipsky, in Bioconjugate Chem., 1995, 6, p 150-165, identified polyethylene glycol as one of the best biocompatible polymers to conjugate with a biologically active compound (such as a drug, a protein, a peptide or an enzyme) to produce a conjugate having improved properties such as compatible solubility characteristics, reduced toxicity, improved surface compatibility, increased circulation time and reduced immunogenicity. [0003] Polyethylene glycol (PEG) is a linear polyoxyalkylene terminated at the ends thereof with hydroxyl groups and generally represented by the formula: HO(CH.sub.2CH.sub.2O).sub.nH. As discussed by Henmanson in Chapter 15 of Bioconjugate Techniques (1996), monomethoxy polyethylene glycol (mPEG) generally represented by the formula: CH.sub.3O(CH.sub.2CH.sub.2O).sub.nH, is usually used to prepare a polyethylene glycol conjugate with a biologically active compound typically by way of a coupling reaction between an amine group of the biologically active compound and an amine receptive derivative (such as trichloro-s-triazine activated mPEG) formed via the remaining terminal hydroxyl group of the monomethoxy polyethylene glycol. [0004] More recently, so called "second generation" PEGylation chemistry has been developed to, for example, minimize problems of diol impurity contamination of mPEG, to increase the molecular weight of the mPEG and to increase stability of the conjugate, see Roberts et al., Advanced Drug Delivery Reviews 54 (2002) p 459-4. U.S. Pat. No. 6,455,639 (herein fully incorporated by reference) described an increased molecular weight mPEG having narrow molecular weight distribution. However, the highest molecular weight disclosed in the '639 patent was 20,861 (weight average molecular weight). It would be a further advance in the art if even higher molecular weight, narrow molecular weight distribution mPEG were discovered along with a processes to produce such a material. SUMMARY OF THE INVENTION [0005] The instant invention is a substituted polyethylene glycol compound having higher molecular weight than has previously been obtained (for example, mPEG molecular weights in excess of 40,000) together with narrow molecular weight dispersion and low diol impurity contamination. The instant invention is also a process for making such materials. [0006] More specifically, the instant invention is a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nH wherein R represents a C.sub.1-7 hydrocarbon group and n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to a number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography. [0007] In another embodiment, the instant invention is a mixture comprising a substituted polyethylene glycol compound and polyethylene glycol, the substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nH wherein R represents a C.sub.1-7 hydrocarbon group; and n represents the average number of moles of C.sub.2H.sub.4O groups added, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight as determined by gel permeation chromatography in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the concentration of the polyethylene glycol being determined by liquid chromatography under critical conditions. [0008] In yet another embodiment, the instant invention is a process for the preparation of a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nY wherein R represents a C.sub.1-7 hydrocarbon group, n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)0-20OH, where R represents a C.sub.1-7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. [0009] In another embodiment, the instant invention is also a process for the preparation of a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nY wherein R represents a C.sub.1-7 hydrocarbon group, n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH.sub.2CH.sub.2).sub.0-20OH, where R represents a C.sub.1-7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. DETAILED DESCRIPTION OF THE INVENTION [0010] The instant invention is a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nH wherein R represents a C.sub.1-7 hydrocarbon group and n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to a number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography. It should be understood that the above weight and number average molecular weights are determined based on all polymer peaks in the chromatogram and not a selected portion thereof. When R is methyl, then the compound is mPEG. Preferably, n is in the range of from 600 to 2000. More preferably, n is in the range of from 700 to 1000. [0011] In another embodiment, the instant invention is a mixture comprising a substituted polyethylene glycol compound and polyethylene glycol, the substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nH wherein R represents a C.sub.1-7 hydrocarbon group; and n represents the average number of moles of C.sub.2H.sub.4O groups added, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight as determined by gel permeation chromatography in the range of from 1 to 1.1, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the concentration of the polyethylene glycol being determined by liquid chromatography under critical conditions. Again, it should be understood that the above weight and number average molecular weights are determined based on the entire chromatogram and not a selected portion thereof. Preferably, n is in the range of from 600 to 2000. More preferably, n is in the range of from 700 to 1000. [0012] Preferably, the amount of polyethylene glycol is less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. More preferably, the amount of polyethylene glycol being less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. A specific critical condition liquid chromatography method for the determination of polyethylene glycol is outlined below. [0013] The process of the instant invention in one embodiment is a process for the preparation of a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nY wherein R represents a C.sub.1-7 hydrocarbon group, n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH.sub.2CH.sub.2).sub.0-20OH, where R represents a C.sub.1-7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound. [0014] The process of the instant invention in another embodiment is process for the preparation of a substituted polyethylene glycol compound having the formula RO(C.sub.2H.sub.4O).sub.nY wherein R represents a C.sub.1-7 hydrocarbon group, n represents the average number of moles of C.sub.2H.sub.4O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH.sub.2CH.sub.2).sub.0-20OH, where R represents a C.sub.1-7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range of from about 0.01 to about 100; (b) contacting the reaction mixture with ethylene oxide so that the ethylene oxide reacts therein to form the substituted polyethylene glycol compound [0015] By definition herein an aprotic polar solvent is an aprotic solvent having a dielectric constant of greater than about 8. Preferably the aprotic polar solvent is a polyether solvent such as bis(2-methoxyethyl)ether. Preferably the alcohol is a methyl ether of an ethylene glycol. A particularly suitable alcohol in the instant invention is diethyleneglycol methyl ether. Preferably, the temperature of reaction in the instant invention is in the range of from about 90 to about 110 degrees Celsius (and more preferably about 100 degrees Celsius). Preferably, the ethylene oxide is contacted with the reaction mixture as a gas under pressure in the range of from about two to about ten atmospheres. Preferably, the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b) is in the range of from about 20 to about 80 weight percent of the reaction mixture. More preferably the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b), in the range of from about 40 to about 60 weight percent of the reaction mixture. [0016] The reaction mixture at the end of step (b) is likely to contain polyethylene glycol. However, it is preferable in the process of the instant invention that the reaction mixture at the end of step (b) contain polyethylene glycol at a concentration of less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. More preferably, such concentration of polyethylene glycol is less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. Most preferably, such concentration of polyethylene glycol is less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. Again, the polyethylene glycol concentration is determined by liquid chromatography under critical conditions. [0017] As discussed above, a the end of step (b) of process the instant invention the substituted polyethylene glycol compound has the formula RO(C.sub.2H.sub.4O).sub.nY where Y is hydrogen or an alkali metal. It should be understood that RO(C.sub.2H.sub.4O).sub.nY is an empirical formula, that Y can be a mixture of hydrogen and an alkali metal and that when Y is an alkali metal the compound may be dissociated. [0018] It is theorized (although it should be understood that applicants are not to be held to such theory) that the use of the preferred polyether aprotic polar solvents (such as bis(2-methoxyethyl) ether) and/or the use of the preferred polyether alcohols (such as diethyleneglycol methyl ether) promote dissociation of the alcohol alkoxide into its respective ions because such solvents and alcohols tend to complex the alkali metal of the alcohol alkoxide. An additional benefit of the use of the preferred polyether aprotic polar solvents that applicants theorize (without being held to such theory) is the like nature of the solvent in relation to the growing polymer chain, thereby further promoting the obtention of higher molecular weight polymer. [0019] With regard to molecular weight distribution, it is theorized (although again it should be understood that applicants are not to be held to such theory) that by using such solvents and alcohols in anionic ethylene oxide polymerizations, the rate of initiation becomes faster with respect to the rate of propagation and that the rate of termination is very small with respect to the rate of propagation. In the typical anionic ethylene oxide polymerization, the rate of initiation is slower that the rate of propagation, and the molecular weight distribution is expected to broaden. However, due to their ability to complex cations, a polyether solvent and a polyether alcohol in the process of the instant invention is theorized to increase the rate of initiation with respect to the rate of propagation and thus promote a narrower molecular weight distribution of the substituted polyethylene glycol compound. A narrow molecular weight distribution of the substituted polyethylene glycol compound is desired for the above discussed PEGylation applications. [0020] Since water initiates ethylene oxide polymerization to form polyethylene glycol ("diol") and since diol is undesired in the substituted polyethylene glycol compound of the instant invention, it is beneficial to minimize the water concentration of the reaction mixture during step (b) of the process of the instant invention. When water is present at the beginning of the reaction, the molecular weight of the PEG will be about two times greater than the molecular weight of the substituted polyethylene compound. There are several potential sources of water, including water in the solvent, alcohol and ethylene oxide; water entering the reactor from outside the reactor, hydroxide in the base; and water generated by dehydration of a polyethylene glycol alcohol. [0021] The polymerization solvent may be dried by, for example, addition of activated molecular sieves. The sieves are removed by filtration before the solvent is added to the polymerization reactor. Alternatively or additionally, the polymerization solvent may be passed through a column of activated alumina to remove water and other protic impurities. An additional column of activated molecular sieves may also be used. By definition herein, the number of moles of akoxide used is the same as the number of moles of base (such as alkali metal or alkali metal hydride) used to produce the alkoxide. The use of potassium hydride to generate the alkoxide is preferred. Continue reading about Polyethylene glycol compounds and process for making... 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